Breaking the heavy-atom paradigm: weak-donor-engineered triplet harvesting in BODIPY photosensitizers for immunogenic pyroptosis therapy

Boron-dipyrromethene (BODIPY)-based dyes emerge as promising agents for phototherapy; however, traditional methods to enhance spin-orbit coupling (SOC) through halogenation introduce dark toxicity and limit therapeutic applications. Here, we present a thiophene-bridged BODIPY functionalized scaffold with carbazole-benzothiophene (Cbz-Bth) substituents at the 2,6-positions. This design employs a weak yet semi-rigid donor to destabilize charge-transfer (CT) states, enabling T₂-mediated spin-orbit charge-transfer intersystem crossing (SOCT-ISC). The resulting photosensitizer, Cbz-Bth-BDP, demonstrates effective reactive oxygen species generation and the photocatalytic transformation of biomolecules such as nicotinamide adenine dinucleotide (NADH) and cytochrome c (Cyt c). Notably, Cbz-Bth-BDP induces pyroptosis by activating gasdermin E (GSDME), leading to cell swelling and the release of intracellular content. In a 3D tumor spheroid model, Cbz-Bth-BDP significantly inhibits tumor growth by reducing adenosine triphosphate (ATP) levels. This study highlights the advantages of accessing higher excited triplet states and positions Cbz-Bth-BDP as a promising, heavy-atom-free photosensitizer for cancer treatment through pyroptosis activation.